Mice with erythropoietin receptor restricted to erythroid tissue become obese, glucose intolerant and insulin resistant. Conversely, wild type mice treated with exogenous erythropoietin exhibit increased hematocrit accompanied with decreased blood glucose, decreased body weight and fat mass, and decreased food intake. We found that in brain, erythropoietin receptor expression in the hypothalamus is localized to neurons that express proopiomelanocortin that is known to suppress appetite. Erythropoietin treatment increased proopiomelanocortin expression in the hypothalamus. Like leptin, erythropoietin stimulation activated STAT3-signaling and up-regulated proopiomelanocortin expression in hypothalamus-derived neural-cultures from wild type mice, but not in neural-cultures derived from mice with erythropoietin receptor restricted to erythroid tissue that also exhibited reduced proopiomelanocortin expression. We found that proopiomelanocortin expression and STAT3 phosphorylation were also reduced in the hypothalamus of mice with erythropoietin receptor restricted to erythroid tissue, with and without erythropoietin treatment. These data show that exogenous erythropoietin regulates STAT3-activation and proopiomelanocortin expression and suggest a link between erythropoietin and leptin response. To investigate the relationship in human between plasma erythropoietin level and metabolic response, we assessed circulating endogenous erythropoietin levels in 109 full heritage Pima Indians from Arizona with increased sensitivity to obesity; we found that erythropoietin levels were negatively associated with percent weight change per year among males, but in opposing directions in females. These data provide evidence that endogenous erythropoietin may be involved in body weight regulation and with a gender specific response. Erythropietin receptor is expressed on muscle progenitor cells and erythropoietin stimulates myoblast proliferation, delays myogenic differentiation and facilitates skeletal muscle repair. Erythropoietin alters expression of skeletal myogenic regulatory factors and other transcription regulatory factors and increases genes associated with slow twitch fibers such as myoglobin. Erythropoietin protective activity to hypoxic stress or ischemic injury in heart and brain is associated with the nitric oxide (NO) pathway. We found that skeletal muscle can act as a potential reservoir for NO precursors. Neuronal nitric oxide synthase (nNOS or NOS1) expression in skeletal muscle contributes to nitric oxide (NO) production which we hypothesize, can be oxidized by oxymyogloibn to nitrate and stored in skeletal muscle. Consistent with this notion, we observed that mice that lack nNOS, particularly in skeletal muscle, exhibit dramtically lower nitrate levels in skeletal muscle and in blood.